Polyethyleneglycols (PEGs) are well known as representative hydrophilic polymers capable of forming hydrogen bonds with water molecules, along with natural polymers and synthetic polymers.
They are soluble in many organic solvents and are nearly nontoxic to humans. Since PEG is completely stretched in water, it may be conjugated with various medications (proteins, peptides, enzymes, genes, etc.) to reduce the toxicity of the medication molecules via steric hindrance and to protect the activity of the medication molecules from the immune system of the human body. Therefore, it may be applied for various medicines to slow clearance from the blood.
Further, when attached to medications having good medicinal effect but being highly toxic and having low solubility, the resultant PEG-drug has improved solubility and reduced toxicity.
In order to introduce PEG to drugs, various functional groups are attached at the end of the PEG chain.
PEG-propionaldehyde is used to increase solubility and efficiency of drugs by conjugation.
PEG-propionaldehyde and methoxy PEG-propionaldehyde (mPEG-propionaldehyde) may be obtained by oxidizing the terminal hydroxyl group of PEG or introducing an acetal group followed by hydrolysis. For example, U.S. Pat. No. 6,465,694 discloses a method for preparation of PEG-aldehyde derivatives, wherein oxygen gas is added to a mixture of PEG and a catalyst to oxidize the —CH2OH group to —CHO. However, the PEG chain may be decomposed under most oxidation conditions. And, the introduction of an acetal group at the end of the PEG chain is commercially inapplicable because the reactants are expensive.
Further, with regard to PEGylation, or the covalent attachment of PEG to a drug, U.S. Pat. No. 4,002,531 (Pierce Chemical Company) discloses a process of oxidizing mPEG (1 K) with MnO2 to prepare mPEG acetaldehyde and attaching it to the enzyme trypsin (PEGylation) for use as a drug delivery system. However, this oxidation reaction may result in increased decomposition of the PEG chain. In addition, the conversion rate is not so high, with 80% or below.
In J. Polym. Sci. Ed, 1984, 22, pp 341-352, PEG-acetaldehyde was prepared from the reaction of PEG (3.4 K) with bromoacetaldehyde to prepare PEG-acetal, followed by hydrolysis. According to the paper, the degree of activation of aldehyde at the terminal group was about 65%, with the remaining −35% remaining as unreacted hydroxyl groups. Thus, it may be inapplicable to a drug delivery system without further purification.
In U.S. Pat. No. 4,002,531 (The University of Alabama in Huntsville), the hydroxyl group at the end of the PEG chain is substituted with highly reactive thiol (—SH) group when PEG is reacted with a small molecule having an acetal group. Considering that PEG-OH has a low reactivity and it is difficult to react it with a single molecule by nucleophilic substitution, it is expected that the degree of activation will not largely different from that reported in J. Polym. Sci. Ed, 1984, 22, pp 341-352 (−65%).
U.S. Pat. No. 5,990,237 (Shearwater Polymers, Inc) presented a method of coupling PEG aldehydes to a variety of water soluble polymers (proteins, enzymes, polypeptides, drugs, dyes, nucleosides, oligonucleotides, lipids, phospholipids, liposomes, etc.) having amine groups, thereby preparing polymers stable in aqueous solution, without easily hydrolyzable groups, e.g. ester, in the polymer chain. However, the purity of PEG aldehydes given in the examples is variable (85-98%) depending on the reaction conditions.
WO 2004/013205 A1 (F. Hoffmann-La Roche AG) and U.S. Pat. No. 6,956,135 B2 (Sun Bio, Inc) presented substances having an aldehyde group at the terminus of the PEG chain but containing carbonyl groups or nitrogens within the PEG chain. They may exhibit different properties from the substances having a PEG chain consisting only of oxygen and hydrogen. Further, since the terminal functional group of the PEG chain is converted without intermediate purification processes, there is a high risk of byproduct (unreacted PEG) generation.